The specific aims are to determine the efficacy and safety of treatment with Ceftriaxone in people with amyotrophic lateral sclerosis (ALS). In a novel attempt to widen the search for potential therapeutic agents, an NINDS led cooperative group performed an in-vitro screening program of 1040 FDA approved drugs in assays relevant to various neurodegenerafive disorders. Several cephalosporins, including Ceftriaxone, were hits in ALS relevant assays including models suggesting increased expression of the astrocytic glutamate transporter, EAAT2 and protection from glutamate and superoxide dismutase mediated toxicity. Ceftriaxone has good CNS penetration and a long half-life. We propose a double-blind, placebo controlled clinical trial of Ceftriaxone in research participants with ALS. The study will determine optimal dosage, safety and efficacy, using a sequential, three STAGE, non- stop drug development design. The first two STAGES are complete. Sixty six subjects enrolled in STAGES 1 and 2 which included a placebo group and two groups receiving either 2 or 4 grams/day of Ceftriaxone. The initial objectives were met. Detailed pharmacokinetic studies showed that Ceftriaxone reached criterion levels in cerebrospinal fluid at both the 2 and 4 gram dosages. At the 4 gram dosage, levels remained above the target level long enough to permit drug holidays if clinically indicated. Both dosages met the prespecified tolerability criterion. Based on these data, an assessment was made that a safe dose can be given to ALS patients that will produce CSF levels reasonably expected to produce a biologic effect. The decision was made to proceed with the STAGE 3 efficacy portion of the study using a dosage of 4 grams daily. The study will be expanded to enroll a total of 600 research participants at centers in US and Canada. Subjects in STAGE 1 and 2 will be rolled over into this larger phase. All participants will continue in the study until the last subject completed 12 months of treatment; The co-primary outcome measures for the STAGE 3 efficacy are the difference in survival between treatment and placebo group at the end of study and the difference in rate of decline in function as measured by the ALS functional rating scales. PUBLIC HEALTH RELEVANCE: Despite advances in understanding the cause of ALS, this remains an untreatable disease. The novel activities of cephalosporins provide a unique opportunity to evaluate a single agent aimed at several pathways important in ALS. Any compound that slews disease course will be immediately clinical important. A positive outcome will enhance our understanding of the underlying biology of motor neuron diseases.